Colchicine Binding Site Tubulin Inhibitors Impair Vincristine-Resistant Neuroblastoma Cell Function

High-risk neuroblastoma remains a clinically challenging pediatric Cancer, with an approximate five-year survival rate of ~60%. Frontline therapy for this group of patients includes surgery and intensive chemotherapy that involves combinations of the tubulin inhibitor vincristine with several Other chemotherapeutics. Unfortunately, unresponsiveness to therapy and relapse are common, with tumors often displaying resistance to vincristine. Recently, we characterized a novel set of tubulin inhibitors that are distinct from vincristine and bind within the colchicine binding site present on tubulin monomers. Colchicine binding site inhibitors (CBSIs) have gained traction as improved chemotherapeutics due to their potential to overcome tubulin inhibitor-induced resistance. In this study, we investigate the functional impact of CBSI treatment on multiple neuroblastoma cell lines, including those that are vincristine-resistant. We demonstrate that our newly developed compounds are effective at disrupting cell division in non-resistant and resistant cells and have cellular activity against vincristine-resistant cell lines. Interestingly, we find that vincristine-resistant cell lines differ in their ability to undergo apoptotic cell death in response to CBSI treatment. Taken together, these findings provide a solid foundation to further investigate the utility of CBSIs for neuroblastoma treatment, while highlighting the distinct resistance mechanisms that can emerge in these childhood cancers.

ALK; MYCN; colchicine binding site inhibitor; neuroblastoma; tubulin; vincristine.